The invention relates to a process for preparing zolpidem.
Zolpidem is a known sedative which has the following structure: 
EP 0 251 859 describes a process for preparing zolpidem. The six-step synthesis starting with a bromoacetophenone is a generally laborious method.
A process for preparing compounds analogous to zolpidem in which 2-aminopyridines and corresponding bromoketoamides are reacted is described in the literature (J. of Med. Chem., 1999, Vol. 42, No.19,3934-3941).
The problem of the present invention is therefore to provide an improved, economical process for preparing zolpidem which can be used on an industrial scale.
The present invention solves the problem outlined above by the method of synthesis described hereinafter.
The invention thus relates to a process for preparing a compound of formula (I) 
wherein
a compound of formula (II) 
wherein
R1 denotes chlorine, bromine, iodine, xe2x80x94Oxe2x80x94COCH3, tosylate or mesylate, is reacted with a compound of formula (III), 
xe2x80x83optionally in a suitable diluent and/or in the presence of a suitable added reagent or catalyst, characterised in that the reaction is carried out in a temperature range from 20 to 80xc2x0 C.
In a particularly preferred process a diluent is used which is selected from among acetonitrile, N-methylpyrrolidinone, tetrahydrofuran, acetone, ethanol and dichloromethane.
In another preferred process, acetonitrile is used as the diluent.
According to the invention, a process in which the reaction is carried out at a temperature of about 60 to 75xc2x0 C., preferably 70xc2x0 C., is particularly important.
Also preferred is a process in which the compound of formula (II) is used in a molar ratio of 1:1 to 1:3 to the compound of formula (III).
Particularly preferred is a process in which the compound of formula (II) is used in a molar ratio of about 1:1.3 to the compound of formula (III).
Most particularly preferred is a process in which an added reagent and/or catalyst is used which is selected from among p-toluenesulphonic acid monohydrate, sodium hydrogen carbonate, sodium acetate, pyridine, dimethylaminopyridine, magnesium sulphate, triethylamine, trimethylorthoformate and tetrabutylammonium bromide.
The invention further relates to the compound of formula (II) 
wherein
R1 denotes bromine.
The present invention also relates to a process for preparing a compound of formula (II), wherein a compound of formula (IV) 
is reacted with elemental bromine in a diluent, preferably dichloromethane.
The reaction of a compound of formula (IV) with elemental bromine is generally carried out at a temperature of 10 to 50xc2x0 C., preferably 15 to 35xc2x0 C., more preferably 18 to 30xc2x0 C., most preferably about 20 or 25xc2x0 C.
The compound of formula IV is generally used in a molar ratio of 1.5 :1 to 1:1.5, preferably about 1:1.2, to elemental bromine.
The invention also relates to the use of compounds of formula (II) for preparing pharmaceutically active compounds.
Preferably, the compound of formula (II) is used to prepare zolpidem.
The invention further relates to a process for preparing a compound of formula (I), this process comprising the following steps:
a) reacting the compound of formula (IV) in an organic diluent at a temperature of 30 to 50xc2x0 C., preferably about 40xc2x0 C., with elemental bromine.
b) washing the reaction mixture with water,
c) after phase separation, concentrating the organic phase by evaporation and optionally diluting it with another organic diluent, and
d) reacting the concentrated organic phase of a) to c) with the compound of formula (III) at 20 to 80xc2x0 C., preferably 60 to 75xc2x0 C., preferably about 70xc2x0 C., without isolating the intermediate product.
The present invention further relates to the use of the compound of formula (I) for preparing the pharmaceutically acceptable salts thereof.
The compound of formula (I) is preferably used to prepare zolpidem semitartrate.
Acids suitable for forming a salt of the compounds according to the invention include, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid, oxalic acid, malonic acid, fumaric acid, maleic acid, tartaric acid, citric acid, ascorbic acid and methanesulphonic acid, particularly tartaric acid.
In a preferred embodiment of the process according to the invention for preparing the compound of formula II, one equivalent of the compound of formula IV is dissolved in a diluent, preferably glacial acetic acid, ethyl acetate, n-butyl acetate or diethylether, most preferably ethyl acetate. A solution of usually 1 to 1.5 equivalents, preferably one equivalent, of bromine is added dropwise in a diluent, preferably ethyl acetate, at a temperature of 40 to 70xc2x0 C., preferably about 45xc2x0 C., and stirred for 2 to 24 h, preferably 5 to 15 h, most preferably 12 h, at a temperature of 10 to 50xc2x0 C., preferably 15 to 35xc2x0 C., more preferably 18 to 30xc2x0 C., most preferably about 20 or 25xc2x0 C. The suspension obtained is filtered, the residue is added to a little water and stirred for about 0.5 to 2 h, preferably about 1 h. The suspension is filtered again and the residue is washed with water. The crystals obtained are dried, preferably in a vacuum drying cupboard at 40 to 80xc2x0 C., preferably at about 70xc2x0 C.
In a preferred embodiment of the process according to the invention for preparing the compound of formula I , about 1 equivalent of the compound of formula (II) is placed in a diluent, for example acetonitrile, and a solution of generally 2 equivalents of the compound of general formula (III) and a diluent, for example acetonitrile, is added dropwise at 20 to 80xc2x0 C., more preferably at 40 to 75xc2x0 C., most preferably at a temperature of about 70xc2x0 C. within 0.5 to 3 h, preferably 1 to 2 h, more preferably about 1.5 or 1.75 h. After it has all been added, the mixture is stirred for 2 to 6 h , preferably 2 to 5 h, more preferably about 2.5 to 3 h.
The reaction mixture is then diluted with a diluent, preferably dichloromethane, and washed one to five times, preferably three times, with water. The organic phase is extracted one to five times with hydrochloric acid, preferably 2 N hydrochloric acid. The combined acid phases are adjusted to a pH of between about 7 and 9, preferably to a pH of about 8, using a base, preferably sodium hydroxide solution, more preferably 20% sodium hydroxide solution. After the reaction mixture has been cooled it is extracted one to five times with an organic diluent, selected from among dichloromethane, toluene, ethyl acetate, n-butyl acetate and methyl-tert.-butylether, preferably dichloromethane and ethyl acetate, more preferably ethyl acetate. The combined organic phases are dried, preferably with magnesium sulphate, and concentrated by evaporation. The product which crystallises out is mixed with a little water and stirred for 5 to 20 h, preferably 15 h, and the crystals are filtered off, washed with water and dried, preferably at 30 to 80xc2x0 C., preferably at 60xc2x0 C., for 1 to 10 h, preferably 5 h.
In a preferred embodiment of the process according to the invention for preparing the semitartrate salt of the compound of general formula I, generally 2 equivalents of the compound of formula I are placed in a diluent, preferably methanol, ethyl acetate, Isopropanol or ethanol, more preferably methanol, and a solution of 1 equivalent of (2R, 3R)-(+)-tartaric acid in a diluent, preferably methanol, ethanol or isopropanol, more preferably methanol, is added.
A precipitation agent, preferably tert.butylmethylether, an isopropanol/methanol-mixture or a methanol/ether mixture, preferably tert.butylmethylether, is optionally added. The mixture is stirred for 1 to 24 h, preferably 12 h, at a temperature of 15 to 30xc2x0 C., preferably at about 20 or 25xc2x0 C. The suspension formed is stirred for a further 0.5 to 3 h, preferably about 1 hour at a temperature of 0 to 20xc2x0 C., preferably 3 to 10xc2x0 C., most preferably at about 5xc2x0 C. The crystals obtained are filtered, optionally washed with a solvent, preferably with tert.butylmethylether, and the crystals are dried, preferably for 1 to 10 h, more preferably for 5 hours at a temperature of 20 to 70xc2x0 C., preferably about 50xc2x0 C.
In a particularly preferred embodiment of the process according to the invention, about 1 equivalent of the compound of formula (IV) is placed in a diluent, for example ethyl acetate, butyl acetate or dichloromethane, preferably dichloromethane, and heated to 30 to 50xc2x0 C., preferably 40xc2x0 C. Preferably, catalytic amounts, preferably 5 to 6 mol-%, of HBr are added to the reaction mixture. Then 1.2 equivalents of bromine are added dropwise. The reaction mixture is stirred for another 60 min, preferably 30 min. The mixture is cooled to about 20 to 25xc2x0 C. and extracted with water. The organic phase is evaporated down to about 10% (v/v) and then diluted with another diluent, preferably tetrahydrofuran, N-methylpyrrolidinone or acetonitrile, preferably acetonitrile. The mixture is added dropwise to a solution of 1.3 equivalents of 6-amino-3-picoline and a diluent, preferably tetrahydrofuran, N-methylpyrrolidinone or acetonitrile, preferably acetonitrile. The resulting mixture is then stirred for about 2 h at 50 to 80xc2x0 C., preferably 70xc2x0 C. The reaction mixture is combined with an organic diluent, preferably toluene, extracted with an aqueous solution, for example 2N hydrochloric acid, and the organic phase is discarded. The aqueous phase is again mixed with an organic diluent, adjusted to a pH of about 4, and the organic phase is discarded again. The extraction step is repeated at a pH of about 8 to 9. After the aqueous phase has been separated off the organic phase is evaporated down to about 10%. The residue is combined with diisopropylether, diethylether or methyl-tert.butylether, preferably methyl-tert.butylether, and stirred for about 30 to 60 minutes at about 0 to 15xc2x0 C., preferably 5xc2x0 C. The crystals formed are washed and dried.
The procedure according to the invention leads to an economical process with a high space-time yield with regard to the compound of formula I or the pharmacologically acceptable salts thereof and a high yield and purity of the intermediate product of formula II, which can be further processed without being isolated or purified by chromatography.